Discovering and developing pharmaceuticals

Obesity : the ‘new’ health issue

Overview of therapeutics in the area

Dr Richard PalmerCEO and R&D Director

Alizyme plc

Obesity : The Problem

Globally > 1 billion overweight adults and > 3 million obese

Major risk for chronic disease Type II diabetes

Cardiovascular disease

Hypertension

Arthritis

Cancer

Key causes are Increased consumption of energy dense food high in fat and sugar

Reduced physical activity

Prevalence of Adult Obesity in Europe BMI 30 Kgm2

Prevalence of Overweight Children Aged Between 4-11 years by Country, Latest Available Year, Europe

Prevalence of overweight children aged between 4-11 years by country, latest available year, Europe

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Russia

Scotla

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Poland

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any

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lavia

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Portu

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International Obesity Task Force (WHO 2004)

Factors Influencing the Development of Obesity

Kopelman, P.G.: Nature 404: 635 – 643, 2000

Obesity Drugs in Phase II and III Clinical Development

Rimonabant CB1 antagonist Sanofi-Aventis

Cetilistat Lipase inhibitor Alizyme

Pramlintide Insulin enhancer Amylin

AOD 9604 Growth Hormone Fraction

Metabolic

APD 356 5-HT2c agonist Arena

Sites to Approach Obesity Treatments

Appetite Suppressants

Appetite Suppressants

Calorie Absorption

Adipose Tissue

Calorie Consumption

Obesity : Solutions?

Marketed Obesity Pharmaceuticals

DRUG Dosing MOA Efficacy Adverse Effects

Sibutramine

(Meridia, Abbott)

Approved 11/97

10 mg po, qd (5 to 15 mg)

Norepinephrine, dopamine, serotonin reuptake inhibitor

2 – 10 kg weight loss

Elevated BP & heart rate

Orlistat

(Xenical®, Roche)

Approved 4/99

120 mg po, tid prior to meals

Inhibits pancreatic lipase blocking fat absorption

2 – 10 kg weight loss

Oily, loose stools, anal leakage, fat soluble vitamins reduced

Only ONE phase 3 drug in development – CB1R antagonist Rimonabant

Obesity Targets

Central 5-HT2c agonists

CB1 antagonists

Appetite suppressant

Appetite suppressant

GI Tract Lipase inhibition

GLP-1/DPP-IV

Ghrelin

CCK agonist

PYY agonist

NPY antagonist

Reduced calorie intake

Satiety

Appetite suppressant

Appetite suppressant

Appetite suppressant

Appetite suppressant

Peripheral MC4R

3 adrenoceptors

DGAT1

Leptin

11 HSD-1

Acetyl CoA carboxylase inhibitor

Appetite suppressant

Metabolic activator

Triglyceride synthesis

Appetite/metabolism

Reduced cortisol

Lipid metabolism

Rimonabant (Acomplia™)

Endocanabinoid system

CB1 receptors : brain, adipocytes, liver

Rimonabant : inhibits food intake

reduces weight, waist circumference

improves insulin sensitivity

central vs. peripheral effects?

Weight loss from baseline

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1

3

5

7

9

3 months 12 months

Wei

ght

loss

(kg

)

Cetilistat placebo Cetilistat Xenical® placebo Xenical®

Acomplia placebo Acomplia Meridia placebo Meridia

Efficacy similar for all agents

Comparative Efficacy of Weight Loss Drugs

Utility of Lipase Inhibitors in Clinical Practice

Inhibition of gastrointestinal lipases attenuates digestion and absorption of dietary fat

Lipase inhibition has proven efficacy in obese patients

Weight loss

Maintenance of lost weight

Secondary benefits of lipase inhibition: prevention and treatment of co-morbid conditions

Non-insulin-dependent diabetes mellitus

Dyslipidaemia

Hypertension

Cetilistat: Urine/Faeces Excretion Profile in Healthy Volunteers

Total Radioactivity

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0 24 48 72 96 120 144 168

Time Point (h)

% A

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Urine Faeces Total

Cetilistat is poorly absorbed

Cetilistat

Phase I

Cetilistat: Phase Ib Programme: Objectives

To demonstrate Cetilistat inhibits GI lipases in healthy volunteers

To demonstrate Cetilistat is safe and well tolerated

To establish doses for further evaluation in Phase II efficacy studies

Cetilistat: Phase Ib Programme: Design

Three studies

Double blind, randomised, placebo-controlled, parallel group

Cohorts of 7-9 healthy male volunteers, resident in Phase I unit

Treatment administered 3 times daily (t.i.d.) with food for 5 days

Cetilistat (50-300 mg t.i.d)

Orlistat (120 mg t.i.d)

Calorie controlled diet (2300 kcal/d, 30% fat)

Ref: Dunk et al (2002) Int. J. Obes. Relat. Metab. Disord. 26, Suppl.1, S2-245

Cetilistat: Phase Ib Study End Points

Primary End Point

Faecal Fat (g/24h)

Secondary End Points

Safety: adverse events, vital signs, ECG, clinical laboratory parameters

Tolerability: gastrointestinal adverse events

Over view of Preliminary Unaudited ResultsPharmacodynamic Effects of Cetilistat and Orlistat (Xenical®)

Placebon = 24

Cetilistat n = 66

Orlistat n = 9

Adverse events(per volunteer)

2.88 2.77 7.33

[ATL-962] mg/tid

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Faeca

l fat (g

/24Hr)

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Orlistat120mg

[ATL-962] mg/tid

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Faeca

l fat (g

/24Hr)

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Orlistat120mg

[ATL-962] mg/tid

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Faeca

l fat (g

/24Hr)

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Orlistat120mg

Correlation of Faecal Fat Excretion and Episodes of Oily Stool

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Faecal fat excretion (g/24h)

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Orlistat

Cetilistat

Phase IIb Study

Ref: Cetilistat (ATL-962), a novel lipase inhibitor : a 12 week randomized placebo controlled study of weight reduction in obese patients. Kopelman et al (submitted)

Cetilistat: Design

20 centres, 5 European countries (UK, Sweden, Finland, Denmark, France)

Placebo, 60 mg tid, 120 mg tid, 240 mg tid

12 weeks treatment

BMI >= 30 kg/m2 with no co-morbidities

BMI > 28 kg/m2 with established untreated co-morbidities

Male and female 18 – 65 years

Calorie deficit (~500 kcal/day)

~30% calories as fat

Behavioural and dietary counselling

Cetilistat: Phase IIb Endpoints

Primary endpoint

Weight loss

Secondary endpoints

Proportion of patients who achieved <5%, 5-10%, >10% weight loss

Reduction in waist/hip ratio

Body Mass Index

Indicators of co-morbidity

• Triglyceride, cholesterol, (HDL/LDL) Fasting glucose, insulin, HbA 1c

Quality of life

Safety and tolerability

• Adverse events, vital signs, fat-soluble vitamins

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8

Placebo 60mg tid

120mgtid

240mgtid

Placebo 120mgtid

Weight loss

(kg)

Absolute Weight Loss

Cetilistat Xenical®

Ref: FDA Medical Review

p<0.002

Week 12 LS Mean change

p<0.0003P=0.005

Comparison of Cetilistat vs Xenical® over Time

Cetilistat week 12 Mean change

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0 12 24 36 52Weeks

Wei

ght

loss

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Xenical Placebo Xenical 60mg tid Xenical 120mg tid Cetilistat/Placebo

Cetilistat 60mg tid Cetilistat 120mg tid Cetilistat 240 tid

Comparison of Cetilistat vs Rimonabant over Time

Cetilistat week 12 Mean change

Rimonabant Placebo Rimonabant 5mg

Cetilistat/Placebo Cetilistat 60mg tid Cetilistat 120mg tid

Cetilistat 240 tid

Rimonabant 20mg

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We

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ITT populationRimonabant weight loss data from completers

% of Patients Completing Treatment who Lost >5% Body Weight

Xenical® at one year (FDA Medical Review)

Cetilistat at 12 weeks

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Placebo 60 mgtid

120 mgtid

240 mgtid

Placebo Xenical

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Cetilistat vs Xenical®: Frequency of GI Adverse Events

Xenical® reference: FDA Medical Review

Frequency following 12 weeks treatment

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Xenical ATL-962 Placebo

Side Effects Of Anti-Obesity Products

With obesity drugs : Efficacy is similar for all agents: Side effect profile is everything!

Lipase Inhibitor Drugs

Oily Spotting Faecal Urgency Flatus with Discharge

Xenical 60mg tid* 18.8% 20.2% 18.9%

Xenical 120mg tid* 26.6% 22.1% 23.9%

ATL-962 Phase IIb** 2.2% 7.9% 1.8%

Centrally Acting DrugsHypertension Nausea CNS

Meridia 7.9% - -

Acomplia - 12.5% ?

* European Public Assessment Report** 3 month data

Cetilistat: Obese Diabetic Study - Design

30 centres, 5 European countries (UK, Sweden, Finland, Denmark, Netherlands)

Placebo, 40 mg tid, 80 mg tid, 120 mg tid for 12 weeks

Orlistat 120 mg tid for 12 weeks

BMI > 28 kg/m2 and < 45 kg/m2

Male and female 18 – 65 years

Type II diabetic and taking metformin

Calorie deficit (~500 kcal/day)

~30% calories as fat

Behavioural and dietary counselling

Results December 2005

Cetilistat: Obese Diabetic Study - Endpoints

Primary endpoint

weight loss

Secondary endpoints

clinical parameters associated with obesity

safety and tolerability (versus placebo and orlistat)

efficacy of orlistat on clinical parameters associated with obesity

ContextContext

Open IND in USA

PK/PD Phase I ongoing

80 obese subjects

14 days dosing

40, 80, 120, 240 mg t.i.d.

Cetilistat: US Development

Conclusions

Obesity is a global epidemic

Drugs show similar efficacy

Side-effects are critical

Many mechanisms being explored

Limited progress over last 10 years

Cetilistat has potential as treatment in future

There is a problem!